The goal of the proposed investigation is to elucidate mucopolysaccharide biochemistry and its malfunctions in Hurler's Syndrome. Hurler's Syndrome is here used in its general connotation to refer to genetic chondrodystrophies, many of which have associated neurological deficits. The primary research model is tissue culture cells derived from patients with different types of mucopolysaccharidoses. These cells are mutants with different genetic blocks in the degradative pathway of mucopolysaccharides. Establishing the nature and pathobiology of specific blocked reactions is a central objective. However, it is axiomatic that an understanding of abnormalities is possible only when normal mechanisms are established. Therefore, elucidation of normal mucopolysaccharide metabolism is also a prime goal of the project. A comparison of the metabolic activities of normal cells with those of mutants will provide understanding of normal as well as abnormal biochemistry. The experimental strategy is to isolate and purify radioactive mucopolysaccharides bio-synthesized by fibroblasts in culture or by developing rat pups. These materials will be used as putative substrates for uptake and degradation studies in intact cell systems and cell-free extracts. For intact cell systems, protein-polysaccharides with minimal modification will be used to study factors such as cell recognition for phagocytosis and sequential degradative order for protein and polysaccharide. Less highly organized material derived by controlled enzyme treatment will be used with intact cells or cell-free extracts to determine whether degradation of mucopolysaccharides follows random, ordered sequence, or "ping-pong" type pathways. Simplified mucopolysaccharide substrates and cell-free extracts will be used to study enzyme defects in specific mutants. Secondary effects of mucopolysaccharide accumulations will be evaluated in fibroblasts with induced inclusion bodies.